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Mycobacteriology Laboratory

Micobatteriologia

Referents: Prof. Maria Rosalia Pasca (Full Professor), Giulia Degiacomi (Associate Professor)

Co-workers: Dr. Deborah Recchia (Post-DOC), Dr. Alessandro Stamilla (Post-DOC), Dr. Ludovica Maci (Post-Doc)

 

1. Search for new antitubercular drugs and study of their mechanisms of action and resistance
Tuberculosis (TB) is the leading cause of death from a single infectious agent, Mycobacterium tuberculosis, and one of the top 10 causes of death globally (WHO, 2025). The circulation and spread of resistant strains of M. tuberculosis represent a serious public health problem. There is therefore an urgent need for new antitubercular drugs that can counteract the phenomenon of drug resistance. The research activity of the Mycobacteriology Laboratory has focused on the development of new compounds with antitubercular activity in the early stages of drug discovery to identify and characterize their mechanisms of action and resistance. The identification and validation of cellular targets are also fundamental in the process of characterizing the mechanism of action of these compounds, including using conditional mutants.
The Mycobacteriology Laboratory has identified the cellular target of benzothiazinones (doi:
10.1126/science.1171583), which are currently in phase II human clinical trials (Macozinone, BTZ043; https://www.newtbdrugs.org/pipeline/clinical). Thanks also to collaborations undertaken during projects funded by the European Commission, we are studying the mechanism of action of new compounds active against M. tuberculosis and validating new cellular targets of M. tuberculosis.
Collaborations:

  • Makarov V (Russian Academy of Science, Mosca, Russia);
  • Mikusova K (Università di Comenius, Bratislava, Slovacchia);
  • Baltas M (CNRS, Tolosa, Francia);
  • Lherbet C (Università Paul Sabatier-Toulouse III, Tolosa, Francia);
  • Manetti F (Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Italia).

2. European Regimen Accelerator For Tuberculosis (ERA4TB; IMI 2 - Horizon 2020)
Since 2020, the Mycobacteriology Laboratory has been one of 31 partners in the European Commission-funded project “European Regimen Accelerator For Tuberculosis” (ERA4TB; IMI 2 - Horizon 2020; Jan. 1, 2020-Dec. 31, 2026), which involves public and private entities with the goal of developing at least two or more new drug combination regimens ready for phase II clinical development (https://era4tb.org/). The Mycobacteriology group has been able to expand its expertise in order to evaluate the intracellular activity of new antitubercular and/or anti-virulence compounds. In particular, ex vivo infection models were developed and implemented both with the THP-1 cell line and using PBMCs (peripheral blood mononuclear cells) in the GLS (granuloma-like structure) test. In this context, we are studying the mechanism of action of compounds currently in Phase 1/2 clinical development and evaluating possible combination therapies using innovative systems.
Collaborations:

  • Cole ST (Pasteur Institute, Parigi, Francia);
  • Ramon-Garcia S (Università di Saragoza, Spagna);
  • Manganelli R (Dipartimento di Medicina Molecolare, Università di Padova, Italia);
  • Baulard A (Institut Pasteur de Lille, Lille, Francia);
  • Khisi Mdluli (Bill & Melinda Gates Medical Research, USA)
  • Natalia Serbina (TB Alliance, USA)

3. PNRR-PE13
The Mycobacteriology Laboratory is also part of the Project: “One Health Basic and Translational Research Actions” funded by MUR (PNRR Extended Partnerships; PE13_INFACT_PNRR - U.A. 14.01; INF-ACT) (11/2022-02/2026).
The main activities in which the Laboratory is involved are the implementation of new strategies to fight antimicrobial resistance in an Italian One Health context. In this project we are studying the mechanism of action/resistance of new drugs against M. tuberculosis (research line 1) and Mycobacterium abscessus (research line 5).
Collaborations:

  • Manganelli R (Dipartimento di Medicina Molecolare, Università di Padova, Italia);
  • Manetti F (Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Italia).

4. Development of antibody-drug conjugation (ADC) strategies for tuberculosis control (PRIN 2022)
M. tuberculosis primarily resides in host macrophages that provide a refuge for the bacteria during infection. To eradicate intracellular M. tuberculosis, we are developing an antibody-drug conjugate (ADC) approach in collaboration with Prof. Petricci and Prof. Bottai. ADCs have been developed for the treatment of oncological diseases and recently adapted to infections caused by Staphylococcus aureus/Pseudomonas aeruginosa and may represent an innovative approach for the treatment of TB. The ADC strategy is based on the use of monoclonal antibodies (mAbs) linked to a cytotoxic/antibiotic drug in a way that allows precise drug delivery to the target.
The lack of commercially available mAbs directed against M. tuberculosis cell surface proteins may hinder the development of ADCs. Therefore, to identify potential candidate ADC molecule targets, we are expressing, by recombinant strains of M. tuberculosis, selected surface antigens modified to have the HA epitope of hemagglutinin as a tag. The HA tag is recognized by commercial anti-HA-specific mAbs. The anti-HA antibodies will be loaded with different payloads (i.e., anti-TB antibiotics). Next, the mAbs will be evaluated for their intracellular activity in in vitro and ex vivo models.
Collaborations:

  • Petricci E (Dipartimento di Biotecnologia, Chimica e Farmacia, Università di Siena, Siena);
  • Bottai D (Dipartimento di Biologia, Università di Pisa, Pisa);
  • Delogu G (Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensive e Perioperatorie,
    Università Cattolica del Sacro Cuore, Roma).

5. Evaluation of the efficacy of the new antibiotic “VOMG” against Mycobacterium abscessus (FFC#9/2023, PNRR-PE13)
Among nontuberculous mycobacteria, Mycobacterium abscessus is becoming the most prevalent pathogen of global concern as it is associated with chronic lung deterioration in people with cystic fibrosis or other chronic lung diseases. M. abscessus is also intrinsically resistant to many drugs. To date, no specific antibiotic has been developed against M. abscessus; therefore, new effective drugs are needed.
Thanks to the funded projects obtained by the Italian Cystic Fibrosis Research Foundation (FFC#19/2018, FFC#14/2020, FFC#18/2021, FC#9/2023, PNRR-PE13), we have characterized the molecule named VOMG (Patents: WO 2024/083764 A1; PCT/EP2025/05993) as a new compound active against M. abscessus and with broad-spectrum activity against other pathogens (doi: 10.1016/j.ijantimicag.2024.107278). We used a multidisciplinary approach including microbiological, chemical, biochemical and transcriptomic analyses to validate VOMG as a promising anti-M. abscessus drug candidate. VOMG inhibits cell division, specifically the enzyme FtsZ. Currently, we are studying in detail the mechanism of action of VOMG and cell division in M. abscessus.
In addition, we are testing the formulation of VOMG in liposomes to increase its bioavailability.
Collaborations:

  • Makarov V (Research Centre of Biotechnology RAS, Mosca, Russia);
  • Ramòn Garcia S. (Università di Zaragoza, Zaragoza, Spagna);
  • Cirillo D (IRCCS Ospedale San Raffaele, Milano);
  • Fraziano M. (Università degli Studi di Roma Tor Vergata, Roma).